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T ranscriptional regulation of neuron-specific genes by neural restrictive silencer

神经限制性沉默子对神经元特异性基因的转录调控

基本信息

批准号：
14390060
负责人：
MORI Nozomu
金额：
$ 8.45万
依托单位：
Nagasaki University (2004)National Institute for Longevity Sciences,NCGG (2002-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

We explored potential roles of the neural restrictive silencing factor NRSF/REST in the following four aspects.1.Mechanisms of transcriptional repression by NRSF via direct interaction with general transcriptional core factors : We found that NRSF binds directly to TBP, so that NRSF would be recruited to the core promoter region to repress transcription of its target genes at the promoter site (Murai et al.,2004).2.Structural analysis of the repression domains of NRSF : In collaboration with Prof.Nishimura's group at Yokohama City University, we are in the process of determining the tertiary structure of the two repression domains of NRSF.3.Determination of the target genes of NRSF : In the promoter region of SCLIP gene, we found a silencer-like element that may contribute to the neuron-specific control of SCLIP. We identified that the N-terminal portion of RB3 contributes to the regulation of microtubule dynamics (Nakao et al.,2004). In collaboration with Prof.Miyata's group at Kagoshima, we identified that the neuronal expression of PACAP gene is under the control of NRSF (Sugawara et al.,2004).4.Potential roles of NRSF in non-neural tissues : In a subset of non-small cell lung cancer, NRSF was found to be deregulated by loosing the interaction with BRM or BRG1 subunit of the SWI/SNF complex for chromatin remodeling. This work is a part of collaboration with Prof.Iba's group at Tokyo Iniversity (Watanabe et al.,submitted).

我们从以下四个方面探讨了神经限制性沉默因子NRSF/REST的潜在作用：1. NRSF通过与一般转录核心因子直接相互作用进行转录抑制的机制：我们发现NRSF直接与TBP结合，因此NRSF将被募集到核心启动子区域，从而在启动子位点抑制其靶基因的转录（Murai et al.，2004).2. NRSF阻遏结构域的结构分析：与横滨市立大学西村教授的研究小组合作，我们正在确定NRSF的两个阻遏结构域的三级结构。3. NRSF靶基因的确定：在SCLIP基因的启动子区域，我们发现了一个类似沉默子的元件，它可能有助于SCLIP的神经元特异性控制。我们确定RB 3的N-末端部分有助于微管动力学的调节（Nakao等人，2004年）。与鹿儿岛的Miyata教授的小组合作，我们确定PACAP基因的神经元表达受NRSF的控制（Sugawara等人，2004).4. NRSF在非神经组织中的潜在作用：在非小细胞肺癌的一个亚组中，发现NRSF通过失去与SWI/SNF复合物的BRM或BRG 1亚基的相互作用而失调，从而进行染色质重塑。这项工作是与东京大学Iba教授小组合作的一部分（Watanabe et al.，提交）。